Criteri di scelta nel trattamento sistemico del carcinoma renale Evidenze cliniche nel trattamento del RCC Alessandro Morabito Unità Sperimentazioni Cliniche Istituto Nazionale Tumori di Napoli Napoli, 14 ottobre 2008
The past IL-2, interferon
IL-2 and IFN in metastatic RCC IL-2 Responses:15% CR: 5% (durable) Survival benefit: not demonstrated in prospective trials Toxicity: significant (high dose...) IFN Responses:10% CR: 2% Survival benefit: increased median survival reported Toxicity: dose correlated...
Advances in last years In understanding the biology and genetics of renal cell carcinoma Availability of novel targeted approaches for the treatment of metastatic RCC
VHL Gene Mutation in Clear-Cell RCC VHL gene mutation: 60% Hypermetilation: 20% VHL complex disrupted HIF accumulation Angiogenesis
New target-based agents Temsirolimus Everolimus Bevacizumab Sunitinib Sorafenib
Target-based agents in RCC: phase 3 trials Inhibitors of VEGF receptors Monoclonal antibody directed against VEGF Inhibitors of mtor
Inhibitors of VEGF receptors
Sunitinib (SU11248)
Sunitinib: phase 2 trials in RCC Two sequentially conducted multicenter phase 2 trials in second-line therapy Endpoint: response rate Overall response: 40% and 34% Stable disease: 28% and 23% Motzer RJ, J Clin Oncol 2006; Motzer RJ, JAMA 2006
Motzer RJ, N Engl J Med 2007 Sunitinib: Phase III Trial for first-line treatment of advanced RCC Study Design: Randomized, Multicenter Trial (Enrollment Complete) Sunitinib 4 wk on/2 wk off: 50 mg/d SUTENT Patients with treatment-naïve mrcc (N=750) 1:1 randomization n=375 n=375 IFN-α (subcutaneous): 9 MU tiw 1 week Primary end-point: Progression-Free Survival
Motzer RJ, N Engl J Med 2007 Progression-Free Survival Median PFS: 11 vs 5 months
Figlin R, ASCO 2008 Overall Survival -value: 0.0128 (Wilcoxon) ore appropriate test when the ratio of death rates between two eatment groups is not constant over time in situations where rvival data may be confounded by crossover or post-study eatments)
Quality of life
Sunitinib: conclusions Author Agent Setting Pts PFS (months) OR (%) OS Motzer (NEJM, 2007) Sunitinib vs IFN 1 st line 750 11 vs 5 (p<0.0001) 31 vs 6 (p<0.001) HR: 0.65 (p=0.02)* Sunitinib has consistently demonstrated improvements in progression-free survival, response rate and overall survival compared to IFN-α Sunitinib provided superior QoL compared with IFNin mrcc patients Sunitinib is the reference standard for the first-line treatment of mrcc
Sorafenib
Methods Study design: randomized discontinuation trial Primary end-point: progression-free survival (PFS) at 12 weeks
Patient flow Tumour Shrinkage 25% (n=73) Continue sorafenib open label (n=79) RCC Sorafenib 12-week run-in (n=202) Tumour growth/ Shrinkage <25% (n=69) Sorafenib 12 weeks (n=32) Placebo* 12 weeks (n=33) % progression free at 24 weeks Tumour growth/ 25% (n=51 ) Off study (n=58) Disease status at 12 weeks unknown (n=9) *Placebo patients who progressed could cross over to sorafenib including 36 patients without bidimensional tumor measurements, but with radiological evidence of progression Ratain, ASCO 2005
Rosner et al. JCO 2002 Randomized discontinuation trial It is a rational phase II study design to demonstrate activity of a possibly cytostatic agent in a disease having substantial patient-to-patient variation in tumor growth rates, and for which disease stabilization is a clinically meaningful measure of activity
Sorafenib: phase 2 results PFS at 12 weeks: 50% with sorafenib vs 18% with placebo (p=0.0077) Median PFS: 24 weeks with sorafenib vs 6 weeks with placebo (p=0.0087)
Sorafenib: Phase III Trial for cytokine pretreated advanced RCC
Progression-free and overall survival P<0.001 P = 0.02 Escudier B, N Engl J Med 2007
Eisen T, JNCI 2008 Sorafenib for older patients: subset analysis > 70 years: 115 Patients
Sorafenib: conclusions Author Agent Setting Pts PFS (months) OR (%) OS Escudier (NEJM, 2007) Sorafenib vs Placebo 2 nd line 903 5.5 vs 2.8 (p<0.001) 10 vs 2 (p<0.001) HR: 0.72 (p=0.02) Sorafenib has demonstrated improvements in PFS compared to placebo Sorafenib is the reference standard for the secondline treatment of cytokine pretreated mrcc
Monoclonal antibody directed against VEGF Bevacizumab Kerbel RS, N Engl J Med 2008
Methods Design: randomized, double-blind, phase 2 trial, comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every two weeks Primary end-point: TTP (time to progression of disease)
p<0.01 RO = 10% (95% CI: 2.9-24.2%) p=0.041 RO = 0%
Escudier B, Lancet 2007
OS PFS
Bukowski RM, Berlin 2008
Bevacizumab: conclusions Author Agent Setting Pts PFS (months) OR (%) OS Escudier (Lancet, 2007) Bevacizumab + IFN vs placebo+ifn 1 st line 649 10.2 vs 5.4 (p<0.0001) 31 vs 13 (p<0.0001) HR: 0.75 (p<0.0026)* Bevacizumab + interferon has demonstrated improvements in PFS compared to interferon + placebo Bevacizumab + interferon can be considered an alternative treatment for the first-line therapy of mrcc
Rini BI, ASCO 2008 Inhibitors of mtor Temsirolimus Everolimus Bevacizumab Sunitinib Sorafenib
Temsirolimus
Temsirolimus: Phase III trial for firstline therapy of poor-risk RCC IFN-α (18 million U three times per week) Advanced RCC No prior therapy KPS 60 (N=626) Temsirolimus (25 mg weekly) Temsirolimus & IFN-α (15 mg weekly; 6 MU twk) Primary end point: Overall Survival Demographics MSKCC poor-risk patients (modified criteria) Predominately clear-cell carcinoma
Poor-risk patients At least three of the following six predictors of short survival were required: LDH > 1.5 times the upper limit of the normal range Hemoglobin level below the lower limit of the normal range Calcium level > 10 mg per deciliter Time from initial diagnosis of renal-cell carcinoma to randomization < 1 year Karnofsky performance score of 60 or 70 Metastases in multiple organs
Temsirolimus vs IFN OS: 10.9 vs 7.3 months HR: 0.73; p=0.008 Temsirolimus vs IFN PFS: 3.8 vs 1.9 months p<0.001
Temsirolimus: conclusions Author Agent Setting Pts PFS (months) OR (%) OS Hudes (NEJM, 2007) Temsirolimus vs IFN vs TEMSR+IFN 1 st line, poor-risk 626 3.7 vs 1.9 vs 3.7 9 vs 7 vs 11 HR: 0.73 (p=0.0069) Temsirolimus as a single agent (25 mg iv weekly) significantly improves outcomes as first-line therapy of poor-risk mrcc patients The combination of temsirolimus + IFN-α did not significantly improve survival vs IFN-α
Everolimus
Jac J, ASCO 2007 Everolimus: phase 2 trial Everolimus is an oral mtor inhibitor Promising anti-tumor activity in patients with pretreated RCC: response rate 32% stable disease 51%
Everolimus: Phase III Trial for advanced RCC patients pretreated with inhibitors of VEGFR Motzer R, ASCO 2008
Motzer R, ASCO 2008
Everolimus: conclusions Author Agent Setting Pts PFS (months) OR (%) OS Motzer (Lancet, 2008) Everolimus vs placebo 2 nd line 410 4.0 vs 1.9 (p<0.001) 1 vs 0 HR: 0.83 (p=0.23) Everolimus is the first and only agent with established clinical benefit for the treatment of patients with advanced renal cancer after therapy with inhibitors of VEGF receptors
RCC Therapeutic algorithm: 2008 Patients Setting Therapy (level 1) Options (level 2) Untreated MSK Risk: good or intermediate Sunitinib or Bevacizumab + IFN HD IL-2 Clinical Trials Observation MSK Risk: poor Temsirolimus Sunitinib Clinical trials Refractory Cytokine refractory Sorafenib Sunitinib Bevacizumab Refractory to angiogenesis inhibitors Everolimus Clinical Trials Investigational
The present : an embarrassment of riches?
Targeted therapies: challenges and future directions Combination therapy New schedules Sequential strategies Role of cytokines New agents Predictive biomarkers Adjuvant and neo-adjuvant therapy
Ongoing studies
Phase III Study of Bevacizumab plus Temsirolimus vs Bevacizumab plus IFN for First-line Treatment of mrcc Eligibility criteria Metastatic RCC No prior systemic treatment No brain metastases (N=800) R A N D O M I S A T I O N Bevacizumab + temsirolimus Bevacizumab + IFN-α Primary end-point: PFS
Randomised Phase III Study of Temsirolimus vs Sorafenib as second-line Therapy in mrcc Eligibility criteria Metastatic clear cell RCC Measurable disease Failed sunitinib Karnofsky PS 70% 1 measurable lesion by RECIST No prior mtor inhibitors No brain metastases N=440 R A N D O M I S A T I O N Temsirolimus 25 mg i.v. + Best supportive care Sorafenib + Best supportive care Primary end-point: PFS NCT00474786. www.clinicaltrials.gov
START: Randomised Phase II Sequential Two-agent Assessment in RCC Therapy Eligibility criteria mrcc of any type PS 0/1 No brain mets No prior systemic therapy (N=240) R A N D O M I S A T I O N (n=120) (n=120) Sunitinib Bevacizumab (n=60) R (n=60) Progression (n=60) R (n=60) Temsirolimus Bevacizumab Sunitinib Temsirolimus tratification: Clear cell vs non clear cell Prior nephrectomy (yes/no) PS (0/1) Objectives: Estimate TTP1 and ORR with each drug (first-line setting) Estimate TTP2 and ORR with each drug (second-line setting) Estimate and rank TTP1 + TTP2 for each sequence
S-TRAC: Sunitinib Phase III Trial in Adjuvant Renal Cancer igh-risk patients ccording to ISS Staging System* =236 Endpoint: Disease-free survival N E P H R E C T O M Y Stratify R A N D O M I S E Sunitinib 50 mg/day 4 weeks on/2 weeks off for 1 year Placebo for 1 year Primary end point: Disease-free survival 3 N0 or NX, M0, Fuhrman s grade 2, ECOG 1 or T4 N0 or NX, M0, any Fuhrman s grade, nd any ECOG status or Any T, N1-2, M0, any uhrman s grade, and any ECOG status Secondary end points: OS, safety, patientrelated outcomes, association of molecular markers with regression - free survival tart Date: September 2007; recruiting NCT00375674. www.clinicaltrials.gov
ASSURE: Adjuvant Sorafenib or Sunitinib for Unfavourable RCC ECOG-sponsored, randomised, double-blind, multicentre phase III trial; currently recruiting on-metastatic RCC isease stage II IV =1332 Duration: 1 year N E P H R E C T O M Y Stratify* R A N D O M I S E Sunitinib 50 mg/day 4 weeks on/2 weeks off Total = 9 cycles Sorafenib 400 mg twice daily for 6 weeks Total = 9 cycles Placebo twice daily for 6 weeks Total = 9 cycles Primary endpoint: DFS ISS (II V); Histologic subtype clear cell/non-clear cell iopsy at recurrence tart Date: May 2006; recruiting NCT00326898. www.clinicaltrials.gov
SORCE: Sorafenib in Patients with Resected Primary RCC at High or Intermediate Risk of Relapse Patients with high- and intermediate- risk resected RCC N=1420 N E P H R E C T O M Y Stratify R A N D O M I S A T I O N Sorafenib 400 mg b.i.d. for 3 years Sorafenib 400 mg b.i.d. for 1 year then placebo for 2 years Placebo for 3 years Endpoint: time to metastases Duration: 1 vs 3 years Start Date: June 2007; recruiting NCT00492258. www.clinicaltrials.gov
In the next years... Ongoing studies will clarify: The role of combination therapy (also including cytokines ) The optimal sequence of therapy Therapy for resistant disease Long term toxicities... Molecular biomarkers defining groups benefiting from anti-vegf therapy